The early detection of Alzheimer's disease (AD) continues to be an important goal, given the staggering medical costs associated with this disease. A major approach has been to examine individuals who are not demented but are at increased genetic risk for AD due to inheritance of the e4 allele of the Apolipoprotein E (APOE) gene. The proposed research addresses several acute unresolved issues concerning the role of APOE-E4 in the development of cognitive deficits leading to AD. To achieve the goal of early detection of AD, individuals should be studied in midlife and not in old age. Also, information-processing tests should be used, so that the cognitive processes underlying a particular deficit can be isolated and linked to brain networks. Finally, to better understand when and how APOE-related cognitive changes lead to the cognitive deficits of AD, longitudinal studies in middle-aged adults are needed. The proposed research will advance the goal of early detection by identifying cognitive and neurobiological markers sensitive to APOE-E4 genotype and showing how those markers in midlife predict the development of subsequent deficits leading to mild cognitive impairment (MCI) and to AD. The longitudinal studies will examine effects of APOE on attention and memory in two cohorts of healthy adults, one in midlife (40-59) and the other older (60-75), as well as in MCI patients. Both US and Norwegian samples of middle-aged and older adults will be assessed, because of the greater frequency of the relatively rare e4 allele among Northern Europeans. For increased sensitivity, behavioral assays of cognitive brain processes will be supplemented with event-related brain potential (ERP) measures. The research will also test the hypothesis that APOE has both a fundamental, modulatory effect as well as domain-specific effects on cognition many years before the onset of AD symptoms. The basic modulatory effect of APOE on cognition may be mediated by axonal pathways, whose integrity will be assessed using magnetic resonance imaging (MRI). Domain-specific effects will be studied by examining the interaction between APOE and neurotransmission genes recently linked to individual differences in attention and memory. The results will have significant implications for the early detection of AD as well as for an improved understanding of the neurocognitive effects of APOE. This in turn may allow for the development of prevention therapies to be provided to those at greatest risk for AD at the earliest possible time.